Towards the synthesis of selective CDK7 inhibitors as potential anti-cancer drugs
Author(s)
Kroll, Sebastian Herbert Benjamin
Type
Thesis
Abstract
Cyclin-dependent kinase 7 (CDK7) exhibits an interesting target for an anti-cancer
therapy approach. CDK7’s triple role in phosphorylation (cell cycle, transcription,
estrogen receptor (ER)) in cell regulation makes this kinase interesting. Phosphorylation
of cell cycle CDK’s via its CAK-complex, of Ser-5 in RNA-PolII as part of the TFIIH-complex
and phosphorylation of Ser-118 in ER all show the importance of this enzyme.
Given that CDKs are over-expressed in many cancers, selective inhibition of CDK7
should result in cell cycle arrest and apoptosis predominately in tumour cells.
Previously, BS-181 (Figure 0.1) has been reported as the first CDK7 selective inhibitor,
which displayed a good in vitro and in vivo profile.1 Based on this initial lead
compound, a library of rational-designed analogues was synthesised. Much of this
library was based on a computer-aided-drug-design (CADD) approach by docking,
which gave valuable insights in possible binding modes and helped to focus targeting
the whole active site. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 0.1: BS-181 and new analogues.
Several of these novel inhibitors showed excellent selectivity versus CDK2 in
particular, and potency against CDK7 in the 30 – 60 nM range for their IC50-values.
Cellular assays confirmed the growth inhibitory properties of these new compounds,
with GI50-values in the low μM range. This work also demonstrates what functional
groups were tolerated in the 3-,5- and 7-position.
1 Ali, S.; Heathcote, D. A.; Kroll, S. H. B.; Jogalekar, A. S.; Scheiper, B.; Patel, H.; Brackow, J.;
Siwicka, A.; Fuchter, M. J.; Periyasamy, M.; Tolhurst, T. S.; Kanneganti, S. K.; Snyder, J. P.; Liotta, D.
C.; Aboagye, E. O.; Barrett, A. G. M.; Coombes, R. C. Cancer Research 2009, 69, 6208.
therapy approach. CDK7’s triple role in phosphorylation (cell cycle, transcription,
estrogen receptor (ER)) in cell regulation makes this kinase interesting. Phosphorylation
of cell cycle CDK’s via its CAK-complex, of Ser-5 in RNA-PolII as part of the TFIIH-complex
and phosphorylation of Ser-118 in ER all show the importance of this enzyme.
Given that CDKs are over-expressed in many cancers, selective inhibition of CDK7
should result in cell cycle arrest and apoptosis predominately in tumour cells.
Previously, BS-181 (Figure 0.1) has been reported as the first CDK7 selective inhibitor,
which displayed a good in vitro and in vivo profile.1 Based on this initial lead
compound, a library of rational-designed analogues was synthesised. Much of this
library was based on a computer-aided-drug-design (CADD) approach by docking,
which gave valuable insights in possible binding modes and helped to focus targeting
the whole active site. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 0.1: BS-181 and new analogues.
Several of these novel inhibitors showed excellent selectivity versus CDK2 in
particular, and potency against CDK7 in the 30 – 60 nM range for their IC50-values.
Cellular assays confirmed the growth inhibitory properties of these new compounds,
with GI50-values in the low μM range. This work also demonstrates what functional
groups were tolerated in the 3-,5- and 7-position.
1 Ali, S.; Heathcote, D. A.; Kroll, S. H. B.; Jogalekar, A. S.; Scheiper, B.; Patel, H.; Brackow, J.;
Siwicka, A.; Fuchter, M. J.; Periyasamy, M.; Tolhurst, T. S.; Kanneganti, S. K.; Snyder, J. P.; Liotta, D.
C.; Aboagye, E. O.; Barrett, A. G. M.; Coombes, R. C. Cancer Research 2009, 69, 6208.
Version
Imperial Users only
Date Issued
2010-09
Date Awarded
2011-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Barrett, Anthony
Sponsor
Cancer Research UK
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)